59 research outputs found
Are hematopoietic stem cells involved in hepatocarcinogenesis?
No full textTHE LIVER HAS THREE CELL LINEAGES ABLE TO PROLIFERATE AFTER A HEPATIC INJURY: the mature hepatocyte, the ductular "bipolar" progenitor cell termed "oval cell" and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue
Lovastatin, but not orlistat, reduces intestinal polyp volume in an Apc(Min/+) mouse model
No full textThe statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and orlistat, an inhibitor of fatty acid synthase (FAS), inhibit tumor cell growth by restricting cholesterol and fatty acid synthesis, respectively. We previously demonstrated that an omega (ω)-3 polyunsaturated fatty acid (PUFA)- or olive oil-enriched diet reduced the polyp number and volume in ApcMin/+ mice. This phenomenon was associated with a significant inhibition of FAS and HMGCoAR, as well as an increase in the estrogen receptor (ER)β/α ratio. Herein, we evaluated the effect of lovastatin and orlistat on polyp development and ER expression in ApcMin/+ mice, in order to confirm previous data obtained with ω-3-PUFAs and olive oil. As expected, the use of lovastatin and orlistat significantly reduced HMGCoAR and FAS enzymatic activities and gene expression in colonic tissues, but did not affect the number of intestinal polyps, while there was a statistically significant reduction in polyp volume only in the mouse group treated with lovastatin. In the mice receiving orlistat, we observed a significant increase in cell proliferation in the polyp tissue, as well as enhanced expression of ERα. Moreover, the overexpression of ERα was associated with a statistically significant increase in PES1, Shh and Gli1 protein levels, considered ERα-related molecular targets
Role of Bone Marrow-Derived Stem Cells in Polyps Development in Mice with ApcMin/+ Mutation
No full textWe explored the hypothesis that an altered microenvironment (intestinal adenomatous polyp) could modify the differentiation program of bone marrow-derived stem cells (BMSCs), involving them in colon carcinogenesis. Sublethally irradiated 8-week-old female ApcMin/+ mice were transplanted with bone marrow (BM) cells obtained from either male age-matched ApcMin/+ (Apc-Tx-Apc) or wild type (WT) (WT-Tx-Apc) mice. At 4 and 7 weeks after transplantation, BM-derived colonocytes were recognized by colocalization of Y-chromosome and Cdx2 protein (specific colonocyte marker). Polyp number, volume, and grade of dysplasia were not influenced by irradiation/transplantation procedures since they were similar in both untreated female ApcMin/+ and Apc-Tx-Apc mice. At 4 and 7 weeks after transplantation, a progressive significant reduction of polyp number and volume was observed in WT-Tx-Apc mice. Moreover, the number of WT-Tx-Apc mice with a high-grade dysplastic polyps significantly decreased as compared to Apc-Tx-Apc mice. Finally, at 4 and 7 weeks after transplantation, WT-Tx-Apc mice showed a progressive significant increase of Y+/Cdx2+ cells in “normal” mucosa, whereas, in the adenomatous tissue, Y+/Cdx2+ cells remained substantially unvaried. Our findings demonstrate that WT BMSCs do not participate in polyp development but rather inhibit their growth. The substitution of genotypically altered colonocytes with Y+/Cdx2+ cells probably contributes to this process
Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study
No full textAIM: To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS: A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS: No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69 vs 37.708 ± 5.31, P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13, P = 0.04), mRNA (2.278 ± 1.19 vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67, P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06 vs 0.532 ± 0.11, P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION: The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study. © 2013 Baishideng. All rights reserved
Imaging modification of colon carcinoma cells exposed to lipid based nanovectors for drug delivery: a scanning electron microscopy investigation
No full textThe adsorption at cell surfaces and cell internalization of two drug delivery lipid based nanovectors has been investigated by means of Field Emission Scanning Electron Microscopy (FE-SEM) operating at low beam voltage on two different colon carcinoma cell lines, CaCo-2 and CoLo-205, that were compared with the M14 melanoma cell line, as a reference. The cells were incubated with the investigated multifunctional nanovectors, based on liposomes and magnetic micelles loaded with 5-fluorouracil, as a chemotherapeutic agent, and a FE-SEM systematic investigation was performed, enabling a detailed imaging of any morphological changes of the drug exposed cells as a function of time. The results of the FE-SEM investigation were validated by MTS assay and immunofluorescence staining of the Ki-67 protein performed on the investigated cell lines at different times. The two nanoformulations resulted in a comparable effect on CaCo-2 and M14 cell lines, while for CoLo 205 cells, the liposomes provided an cytotoxic activity higher than that observed in the case of the micelles. The study highlighted the high potential of FE-SEM as a valuable complementary technique for imaging and monitoring in time the drug effects on the selected cells exposed to the two different nanoformulations
Exosome Released FZD10 Increases Ki-67 Expression via Phospho-ERK1/2 in Colorectal and Gastric Cancer
No full textFrizzled (FZD) proteins are primary receptors for Wnt signaling that activates the mitogen-activated protein kinase (MAPK) pathways. Dysfunction of Wnt signals with consequently abnormal activation of MAPK3 pathways was found in colorectal cancer (CRC) and gastric cancer (GC). Upregulation of FZD10 protein, localized in the exosomes isolated from plasma of CRC and GC patients, was associated with a poor prognosis. Herein, the expression levels of circulating FZD10 were found to be strongly correlated to their expression levels in the corresponding tissues in CRC and GC patients. Bioinformatic prediction revealed a link between FZD10 and Ki-67 through MAPK3. In both CRC and GC tissues, pERK1/2 levels were significantly increased at more advanced disease stages, and pERK1/2 and Ki-67 were correlated. Silencing of FZD10 in CRC and GC cells resulted in a significant reduction of pERK1/2 and Ki-67 expression, while subsequent treatment with exogenous exosomes partially restored their expression levels. The strong correlation between the expression of Ki-67 in tissues and of FZD10 in exosomes suggests that the exosome-delivered FZD10 may be a promising novel prognostic and diagnostic biomarker for CRC and GC
FZD10 Carried by Exosomes Sustains Cancer Cell Proliferation
No full textExtracellular vesicles (EVs) are involved in intercellular communication during carcinogenesis, and cancer cells are able to secrete EVs, in particular exosomes containing molecules, that can be transferred to recipient cells to induce pathological processes and significant modifications, as metastasis, increase of proliferation, and carcinogenesis evolution. FZD proteins, a family of receptors comprised in the Wnt signaling pathway, play an important role in carcinogenesis of the gastroenteric tract. Here, a still unknown role of Frizzled 10 (FZD10) protein was identified. In particular, the presence of FZD10 and FZD10-mRNA in exosomes extracted from culture medium of the untreated colorectal, gastric, hepatic, and cholangio cancer cell lines, was detected. A substantial reduction in the FZD10 and FZD10-mRNA level was achieved in FZD10-mRNA silenced cells and in their corresponding exosomes. Concomitantly, a significant decrease in viability of the silenced cells compared to their respective controls was observed. Notably, the incubation of silenced cells with the exosomes extracted from culture medium of the same untreated cells promoted the restoration of the cell viability and, also, of the FZD10 and FZD10-mRNA level, thus indicating that the FZD10 and FZD10-mRNA delivering exosomes may be potential messengers of cancer reactivation and play an active role in long-distance metastatization
The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel mediated resistance in gastric cancer cell lines
No full textIntroduction: Paclitaxel (PTX) interferes with microtubule architecture by binding
to b-tubulin, thereby blocking progression at the G2/M phase and inducing apoptosis. This study aimed to investigate molecular processes underlying PTXmediated resistance in gastric cancer (GC) cells. Methods: PTX-mediated resistance involves many processes, and in this work some of the factors involved in the resistance mechanism were identified by comparing two GC lines with PTX induced resistance to their sensitive counterparts. Results: Thus, the key feature of PTX-resistant cells was the overexpression of proangiogenic factors such as VEGFA, VEGFC, and Ang2, known to support tumor cell
growth. A second relevant change detected in PTX-resistant lines was the elevated level of TUBbIII, a tubulin isoform that opposes microtubule stabilization. A third identified factor contributing to PTX-resistance was P-glycoprotein (P-gp), a transporter responsible for chemotherapy efflux from the cells, highly expressed in PTX-resistant lines. Discussion : These findings were in line with a greater sensitivity of resistant cells
to treatment with both Ramucirumab and Elacridar. Ramucirumab significantly reduced the expression of angiogenic molecules and TUBbIII, while Elacridar restored the access of chemotherapy, recovering its anti-mitotic and proapoptotic effects. Finally, this study highlighted the role played by exosomes in spreading factors responsible for resistance in the tumor microenvironment
Multistage vector delivery of sulindac and silymarin for prevention of colon cancer
No full textFamilial adenomatous polyposis (FAP) is an inherited condition secondary to germline mutations in the APC gene, thus resulting in the formation of hundreds of colonic adenomas that eventually progress into colon cancer. Surgical removal of the colon remains the only treatment option to avoid malignancy, as long-term exposure to chemopreventive agents such as sulindac (a non-steroidal anti-inflammatory drug) and silymarin (phytoestrogen) is not feasible. Here, we have developed a multistage silicon-based drug delivery platform for sulindac and silymarin that preferentially interacts with colon cancer cells as opposed to normal intestinal mucosa. Preferential binding and internalization of these drugs into colon cancer cells was obtained using a targeting strategy against the protein meprin A, which we demonstrate is overexpressed in human colon cancer cells and in the small intestine of Apc(Min/+) mice. We propose that this delivery system could potentially be used to reduce drug-induced side effects in FAP patients, thus enabling long-term prevention of adenoma formation. (C) 2015 Elsevier B.V. All rights reserved
NIR-Absorbing Mesoporous Silica-Coated Copper Sulphide Nanostructures for Light-to-Thermal Energy Conversion
No full textPlasmonic nanostructures, featuring near infrared (NIR)-absorption, are rising as efficient nanosystems for in vitro photothermal (PT) studies and in vivo PT treatment of cancer diseases. Among the different materials, new plasmonic nanostructures based on Cu(2−x)S nanocrystals (NCs) are emerging as valuable alternatives to Au nanorods, nanostars and nanoshells, largely exploited as NIR absorbing nanoheaters. Even though Cu(2−x)S plasmonic properties are not linked to geometry, the role played by their size, shape and surface chemistry is expected to be fundamental for an efficient PT process. Here, Cu(2−x)S NCs coated with a hydrophilic mesoporous silica shell (MSS) are synthesized by solution-phase strategies, tuning the core geometry, MSS thickness and texture. Besides their loading capability, the silica shell has been widely reported to provide a more robust plasmonic core protection than organic molecular/polymeric coatings, and improved heat flow from the NC to the environment due to a reduced interfacial thermal resistance and direct electron–phonon coupling through the interface. Systematic structural and morphological analysis of the core-shell nanoparticles and an in-depth thermoplasmonic characterization by using a pump beam 808 nm laser, are carried out. The results suggest that large triangular nanoplates (NPLs) coated by a few tens of nanometers thick MSS, show good photostability under laser light irradiation and provide a temperature increase above 38 °C and a 20% PT efficiency upon short irradiation time (60 s) at 6 W/cm(2) power density
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